AMPK/PPARα/SCAD信号途径对心肌肥大的调控研究

目的:研究短链酰基辅酶A脱氢酶(short-chain acyl-coenzyme A dehydrogenase,SCAD)在心肌细胞肥大中的作用及腺苷酸活化蛋白激酶(adenosine monophosphate-activated protein kinase,AMPK)/过氧化物酶体增殖剂活化受体α(peroxisome proliferator-activated receptorα,PPARα)信号途径对SCAD的调控作用。方法:使用Western blotting和RT-PCR筛选干扰SCAD的最优序列,并使用非诺贝特(10μmol/L)提前干预24 h后给予干扰序列,观察SCAD的mRNA、蛋白表达和酶活性以及脂质代谢和心肌细胞表面积的改变。采用RT-PCR检测心肌细胞内肥大标志物心房利钠因子(atrial natriuretic factor,ANF)和脑利钠肽(brain natriuretic peptide,BNP)mRNA水平,以明确心肌细胞是否发生肥大。分别用10μmol/L非诺贝特和0.5 mmol/L 5-氨基咪唑-4-甲酰胺核糖核苷酸(5-aminoimidazole-4-carboxamide ribonucleotide,AICAR)预处理心肌细胞30 min,用20μmol/L苯肾上腺素(phenylephrine,PE)刺激24 h,观察心肌细胞表面积和游离脂肪酸含量的变化,并采用Western blotting和RT-PCR检测p-AMPKα、PPARα和SCAD在蛋白和mRNA水平的变化。结果:筛选出的最优干扰序列siRNA-1186和PE诱导的心肌细胞肥大趋势一致,与对照组比较,敲低SCAD表达组的心肌细胞ANF和BNP水平显著升高,心肌细胞表面积明显增大,心肌细胞游离脂肪酸含量明显增加。非诺贝特预处理可显著上调PPARα和SCAD的表达,增加SCAD的酶活性,降低心肌细胞的游离脂肪酸含量,预防敲低SCAD引起的心肌细胞肥大。与对照组比较,PE处理组中p-AMPKα(T172)、PPARα和SCAD的蛋白及mRNA水平均明显下调,SCAD的酶活性下降;与PE组相比,用非诺贝特或AICAR预处理30 min组的心肌细胞表面积明显减少,心肌细胞游离脂肪酸含量明显降低,p-AMPKα、PPARα和SCAD蛋白及mRNA水平均明显上调,SCAD的酶活性增加。结论:SCAD表达下调与心肌细胞肥大及其能量代谢密切相关;AMPK/PPARα/SCAD信号途径对心肌肥大可能具有直接的调控作用。     

短链酰基辅酶A脱氢酶在大鼠生理性和病理性心肌肥大中的作用

 目的：研究短链酰基辅酶A脱氢酶(short-chain acyl-CoA dehydrogenase, SCAD)在大鼠生理性和病理性心肌肥大中的变化,探讨其与心肌肥大之间的关系。方法：以自发性高血压大鼠作为病理性心肌肥大模型,游泳运动训练性大鼠作为生理性心肌肥大模型。检测大鼠的血压、左室重量指数、血清和心肌游离脂肪酸含量、SCAD mRNA、蛋白表达及其酶活性的变化,采用超声心动图观察心脏的结构及功能。结果：与对照组比较,运动组大鼠出现了明显的离心性肥大,心肌收缩功能增强;而高血压组大鼠呈现出明显的向心性肥大,心肌收缩功能减退。与对照组比较,运动组和高血压组大鼠的左室重量指数均明显增高,但两组间比较无显著差异,二者发生了相同程度的心肌肥大。与对照组比较,运动组大鼠左心室SCAD mRNA和蛋白表达均明显上调,酶活性增高,血清和心肌游离脂肪酸含量明显减少;而自发性高血压大鼠左心室SCAD mRNA和蛋白表达均明显下调,酶活性下降,血清和心肌游离脂肪酸含量明显增多。结论：SCAD在生理性和病理性心肌肥大中呈现出不一致的变化趋势,可能作为区别2种不同心肌肥大的分子标志物以及病理性心肌肥大的潜在治疗靶点。     

短链酰基辅酶A脱氢酶在心肌细胞凋亡中的作用

目的:研究短链酰基辅酶A脱氢酶(short-chain acyl-Co A dehydrogenase,SCAD)在心肌细胞凋亡中的变化,探讨其与心肌细胞凋亡之间的关系。方法:以叔丁基过氧化氢(tert-butyl hydroperoxide,t BHP)刺激心肌细胞建立凋亡模型。检测细胞存活率、SCAD mRNA和蛋白表达、SCAD活性以及游离脂肪酸含量变化;并采用SCAD的最优干扰序列siRNA-1186进行干扰,观察其对心肌细胞凋亡的影响。结果:与对照组相比,在t BHP诱导的心肌细胞凋亡模型中,SCAD的mRNA和蛋白表达均显著下调。与阴性对照序列组相比,siRNA-1186干扰后心肌细胞的SCAD表达和活性明显下降,心肌细胞游离脂肪酸含量明显增加,同时,心肌细胞出现了明显凋亡,与t BHP诱导的心肌细胞凋亡趋势一致。结论:SCAD表达失调可能参与心肌细胞凋亡的过程,上调SCAD可能成为干预心肌细胞凋亡的重要环节之一。     

ERK信号通路介导的EP300过表达在苯肾上腺素诱导小鼠心肌细胞肥大中的作用

目的:探讨细胞外信号调节激酶(ERK)信号通路介导的E1A结合蛋白p300(EP300)过表达在苯肾上腺素(PE)诱导的小鼠心肌细胞肥大中的作用。方法:原代培养新生小鼠心肌细胞,按照随机数字表法分为:正常组、生理盐水(NS)组、PE组、溶剂对照组、漆树酸(AA)组、ERK抑制剂组和AA+ERK抑制剂组。收集干预48 h的小鼠心肌细胞,采用Western blot检测ERK、第9位赖氨酸乙酰化的组蛋白H3(H3K9ac)和β-肌球蛋白重链(β-MHC)的蛋白表达水平;RT-qPCR检测心肌细胞肥大标志物β-MHC的mRNA表达水平;免疫共沉淀验证EP300与H3K9ac之间的调控关系;免疫荧光染色及Western blot检测心肌细胞中EP300的表达水平。结果:Western blot结果表明小鼠心肌细胞中H3K9ac水平在PE组显著高于生理盐水对照组(P0.05);Western blot及免疫荧光结果表明PE组EP300表达水平显著高于生理盐水对照组(P0.05);免疫共沉淀结果表明EP300与H3K9ac之间能够相互结合;PE组p-ERK蛋白水平及β-MHC的mRNA和蛋白水平均显著高于NS组(P0.05);而ERK抑制剂组及AA组EP300、H3K9ac、β-MHC及p-ERK水平均显著低于PE组(P0.05)。结论:EP300介导的H3K9ac高乙酰化参与了PE诱导的小鼠心肌细胞肥大,而ERK信号通路可能是AA减轻PE诱导的心肌肥厚的信号通路之一。     

胰岛素样生长因子-1通过细胞外信号调节激酶1/2通路下调转录因子基本转录元件结合蛋白表达抗心肌细胞凋亡

目的 探讨胰岛素样生长因子-1(IGF-1)对大鼠心肌细胞凋亡保护作用的基因调控机制。方法 体外培养新生大鼠心肌细胞,10nmol/L IGF-1刺激的同时,分别加入磷脂酰肌醇-3激酶（PI3K）、细胞外信号调节激酶（ERK）1/2和Raf-1 3条通路抑制剂（20μmol/L）,通过RT-PCR及Western blotting方法观察IGF-1调节基本转录元件结合蛋白（BTEB）的基因表达及其通路调控。100μmol/L H2O2处理诱导心肌细胞凋亡,通过DNA梯度分析、Annexin V-FITC/PI双染色法、Caspase-3活性测定、Hoechest33258染色法观察用BTEB特异性siRNA人为下调BTEB基因表达后对心肌细胞凋亡的影响。结果 大鼠心肌细胞经IGF-1刺激60min后,BTEB mRNA和蛋白表达均明显下降;与对照组相比,加入ERK1/2通路抑制剂PD98059组BTEB的mRNA和蛋白表达均明显增高（P＜0.01）;H2O2诱导的大鼠心肌细胞于下调BTEB表达后,DNA片段化改善,心肌细胞凋亡率下降（P＜0.05）,Caspase-3活性降低（P＜0.05）,凋亡小体减少,与IGF-1的抗心肌细胞凋亡效果相似。
结论 IGF-1可以通过ERK1/2通路下调转录因子BTEB基因表达而发挥抗心肌细胞凋亡的作用。     

短链酰基辅酶A脱氢酶在心脏成纤维细胞胶原表达和细胞增殖中的作用

目的:研究短链酰基辅酶A脱氢酶(short-chain acyl-CoA dehydrogenase,SCAD)在心脏成纤维细胞胶原表达和细胞增殖中的作用,探讨其与心肌纤维化之间的关系。方法:以血管紧张素Ⅱ(angiotensin Ⅱ,Ang Ⅱ)刺激心脏成纤维细胞建立胶原表达和细胞增殖模型,并采用SCAD的最优干扰序列siRNA-1186进行干扰,检测SCAD的mRNA、蛋白表达、酶活性、脂肪酸β氧化速率、ATP以及游离脂肪酸含量的变化;观察其对心脏成纤维细胞胶原表达和细胞增殖的影响。结果:与对照组相比,在Ang Ⅱ诱导的心脏成纤维细胞增殖和胶原表达模型中,SCAD的mRNA和蛋白表达均显著下调。与阴性对照序列组相比,siRNA-1186干扰后心脏成纤维细胞的SCAD表达和酶活性明显下降,心脏成纤维细胞脂肪酸β氧化速率以及ATP生成明显降低,并且游离脂肪酸含量明显增多。同时,心脏成纤维细胞出现明显增殖,Ⅰ、Ⅲ型胶原的表达明显增加。结论:SCAD表达失调可能导致了心脏成纤维细胞异常增殖、胶原分泌紊乱,上调SCAD可能成为干预心肌纤维化的重要环节之一。     

泛素E3连接酶TRIM10在心肌细胞肥大中的作用

目的:探讨泛素E3连接酶TRIM10在心肌细胞肥大中的作用及分子机制。方法:培养原代的大鼠乳鼠心肌细胞,siRNA-TRIM10与siRNA对照(siRNA-control)或过表达腺病毒Ad-TRIM10与空载对照Ad-GFP转染细胞24 h,然后用苯肾上腺素(phenylephrine,PE)处理细胞24 h。Western blot检测TRIM10、AKT和ERK1/2的蛋白水平;免疫荧光染色观察心肌细胞的大小;实时荧光定量PCR检测心房钠尿肽(ANP)和脑钠尿肽(BNP)的mRNA的表达水平。结果:与对照组相比,PE处理明显上调心肌细胞中TRIM10蛋白的表达水平。siRNA-TRIM10敲低内源性TRIM10表达后明显减小PE诱导的心肌细胞体积,抑制ANP和BNP的mRNA的表达以及降低AKT和ERK1/2的磷酸化水平;而过表达TRIM10则呈现出与siRNA-TRIM10完全相反的结果。结论:TRIM10可调节心肌细胞肥大,其作用可能与AKT和ERK信号相关。     

短链酰基辅酶A脱氢酶在大鼠心脏发育中的表达及其与心肌肥厚的关系

 目的：研究大鼠心脏发育过程中短链酰基辅酶A脱氢酶(short-chain acyl-CoA dehydrogenase, SCAD)的表达变化规律,并探讨其与高血压大鼠心肌肥厚的关系。方法：观察不同时期Wistar大鼠和不同周龄自发性高血压大鼠心肌组织的SCAD蛋白表达及酶活性变化,检测大鼠的血清和心肌游离脂肪酸含量。结果：与胚胎期19 d Wistar大鼠组比较,出生后1 d、2周、6周及16周龄Wistar大鼠组心肌的SCAD蛋白表达及酶活性增加,血清和心肌游离脂肪酸含量明显减少,二者之间呈负相关,其中,从2周龄Wistar大鼠组开始差异有统计学意义。与周龄匹配的WKY大鼠组比较,2周龄自发性高血压大鼠组收缩压尚未升高,6周龄及16周龄自发性高血压大鼠组收缩压显著增高;各时点自发性高血压大鼠组的左室重量指数均明显增高,提示自发性高血压大鼠在血压升高之前,已经发生了明显的心肌肥厚。与周龄匹配的WKY大鼠组比较,2周、6周及16周龄自发性高血压大鼠组心肌的SCAD蛋白表达及酶活性明显下降,血清和心肌游离脂肪酸含量明显增加,呈显著负相关。结论：(1)SCAD蛋白表达随大鼠心脏的生长发育逐渐上调,可能与心脏对脂肪酸的利用增加密切相关。(2)SCAD的蛋白表达及其酶活性显著下降, 可能是导致自发性高血压大鼠肥厚心肌能量代谢“胚胎型再演”的分子基础。     

睾酮诱导大鼠心肌细胞肥大反应并上调ERK1/2蛋白表达

目的探讨细胞外信号调节激酶(ERK1/2蛋白)在睾酮对大鼠心肌肥大中的作用。方法用差速贴壁法分离及纯化培养新生SD大鼠心肌细胞,以Bradford法测定心肌细胞蛋白质含量,同位素法分析3H-亮氨酸(3H-Leu)掺入,IBAS图像分析心肌细胞表面积,以免疫印迹法检测心肌细胞ERK1/2蛋白表达水平。结果生理浓度的T作用于大鼠心肌细胞24 h后,细胞蛋白质含量3、H-Leu掺入和细胞表面积均增加,其中以10-8mol/L作用最强。雄激素受体拮抗剂氟他胺(Flu)10-5mol/L预处理2 h可抑制T诱导的心肌细胞蛋白质含量的增加,而Flu单独作用对心肌细胞蛋白质含量无影响。ERK1/2信号通路的特异性抑制剂PD98059 50μmol/L预处理2 h,可抑制T诱导的心肌细胞3H-Leu掺入的增加;10-8mol/L T作用24 h使心肌细胞的ERK1/2的蛋白表达显著增加;10-5mol/L Flu预处理2 h可逆转T诱导的心肌细胞ERK1/2蛋白表达的增加。结论生理浓度的T可以诱导心肌细胞肥大反应,该作用可能由ERK1/2信号通路介导。T通过雄激素受体(AR)上调ERK1/2蛋白表达。     

短链酰基辅酶A脱氢酶在高血压血管重构中的作用

目的:研究短链酰基辅酶A脱氢酶(short-chain acyl-CoA dehydrogenase,SCAD)在高血压血管重构中的变化,探讨SCAD与高血压血管重构之间的关系。方法:采用游泳耐力训练方式训练16周龄的自发性高血压大鼠(spontaneously hypertensive rats,SHR)和健康Wistar大鼠8周,分别以24周龄的SHR和Wistar大鼠作为实验对照,定期测量鼠尾收缩压,测定各组大鼠胸主动脉血管腔内径和血管壁中层厚度、SCAD的mRNA和蛋白表达水平、SCAD酶活性的变化、ATP和ROS水平及血清和胸主动脉游离脂肪酸含量。结果:与Wistar组比较,SHR组大鼠血压升高,血管腔内径减小,血管壁中层厚度增大,血管壁中层厚度与血管腔内径比值增大;与SHR组相比,SHR游泳组血压下降,血管腔内径增大,血管壁中层厚度减小,血管壁中层厚度与血管腔内径比值减小(P0.05)。与Wistar组比较,SHR组大鼠主动脉SCAD的mRNA和蛋白表达水平显著下调,主动脉中SCAD酶活性下降,ATP含量降低,血清和主动脉游离脂肪酸含量明显增加,ROS含量增加;分别与Wistar组和SHR组比较,Wistar游泳组和SHR游泳组主动脉SCAD的mRNA和蛋白表达水平均明显上调,主动脉中SCAD的酶活性增高,ATP含量增加,血清和主动脉的游离脂肪酸含量明显减少,ROS含量减少。结论:主动脉SCAD的表达下调可能与高血压血管重构密切相关。游泳运动可能通过上调SCAD表达,从而逆转高血压血管重构。     

Decreased KCNE2 expression participates in the development of cardiac hypertrophy

AIM: To investigate whether KCNE2 participates in the development of pathological hypertrophy. METHODS: Bidirectional manipulations of KCNE2 expression were performed by adenoviral overexpression of KCNE2 or knockdown of KCNE2 with RNA interference in PE-induced neonatal rat ventricular myocytes. Then overexpression of KCNE2 in mouse model of left ventricular hypertrophy induced by transverse aortic constriction( TAC) by ultrasound microbubble-mediated gene transfer were used to detect the therapeutic function of KCNE2 in the development of hypertrophy. RESULTS: KCNE2 expression was significantly decreased in PE-induced hypertrophic cardiomyocytes and in hypertrophic hearts produced by TAC. Knockdown of KCNE2 in cardiomyocytes reproduced hypertrophy,whereas overexpression of KCNE2 attenuated PE-induced cardiomyocyte hypertrophy. Knockdown of KCNE2 increased calcineurin activity and nuclear NFAT protein level,and pretreatment with nifedipine or FK506 attenuated decreased KCNE2-induced cardiomyocyte hypertrophy. Overexpression of KCNE2 in heart by ultrasound microbubble-mediated gene transfer suppressed the development of hypertrophy and activation of calcineurin-NFAT and MAPK pathways in TAC mice. CONCLUSION: These findings demonstrate that cardiac KCNE2 expression is decreased and contributes to the development of hypertrophy via activation of calcineurin-NFAT and MAPK pathways.     

PARP-2在大鼠心肌肥大中的作用

目的:在细胞和整体水平研究多聚腺苷酸二磷酸核糖基聚合酶2(PARP-2)在心肌肥大过程中表达的变化规律以及PARP-2对心肌肥大的调控作用。方法:健康雄性SD大鼠采用腹主动脉缩窄法(AAC)建立心肌肥大动物模型,采用real-time PCR和Western blot检测PARP-2的mRNA和蛋白表达变化;使用PARP-2特异性的siRNA干扰序列来处理细胞后,通过检测心肌细胞表面积及ANF、BNP和β-MHC的mRNA表达变化来作为评判心肌细胞肥大状况。结果:AAC大鼠心脏组织中PARP-2的蛋白和mRNA表达均显著上调;在AngⅡ诱导的心肌细胞肥大模型中,AngⅡ能时间和剂量依赖性地上调PARP-2的mRNA和蛋白表达;用siRNA干扰序列沉默PARP-2能够逆转AngⅡ所诱导心肌细胞的肥大。结论:在AngⅡ诱导的心肌细胞肥大的体外模型和腹主动脉缩窄诱导的心肌肥大动物的体内模型中,PARP-2的mRNA和蛋白水平均显著上调;特异性沉默PARP-2能够抑制AngⅡ诱导的心肌细胞肥大。     

不同年龄高血压大鼠心肌中MKP-1的表达及对心肌肥厚的影响

目的：研究不同年龄的自发性高血压大鼠（SHR）和Wistar Kyoto大鼠（WKY）心室肌组织中丝裂原活化蛋白激酶（MAPK）及其磷酸酶（MKP-1）的表达以及与心肌肥厚的关系。方法： 用左心室重量与体重的比值作为心肌肥大指数并以此指标反映心肌肥厚；分别用Western blotting方法和RT-PCR法半定量测定心室肌组织中磷酸化细胞外信号调节激酶（p-ERK）的蛋白表达和MKP-1 mRNA的含量。结果： （1）SHR的血压自8周龄起明显高于WKY（P<0.01），心肌肥大指数明显大于WKY（P<0.05），ERK和MKP-1的表达均比WKY高（P<0.05）；（2）SHR的血压随年龄增长而升高（P<0.05），至14周趋于稳定，心肌肥大指数则在24周时出现激增（P<0.01）；（3）p-ERK随年龄增长呈递增趋势，而MKP-1呈递减趋势，且与心肌肥大指数和ERK的表达呈负相关（P<0.01）。结论： MKP-1在高血压大鼠随年龄和血压增加的心肌肥厚过程中起重要作用，其表达逐渐下降可能是导致ERK激活增加，进而引起心肌细胞肥大的重要原因。     

Cinnamaldehyde attenuates pressure overload-induced cardiac hypertrophy

Background: Cinnamaldehyde is a major bioactive compound isolated from the leaves of Cinnamomum osmophloeum. Studies have demonstrated that cinnamaldehyde has anti-bacterial activity, anti-tumorigenic effect, immunomodulatory effect, anti-fungal activity, anti-oxidative effect, anti-inflammatory and anti-diabetic effect. It has been proven that Cinnamaldehyde improves ischemia/reperfusion injury of pre-treatment. However, little is known about the effect of cinnamaldehyde on cardiac hypertrophy. Methods: Aortic banding (AB) was performed to induce cardiac hypertrophy in mice. Cinnamaldehyde premixed in diets was administered to mice after one week of AB. Echocardiography and catheter-based measurements of hemodynamic parameters were performed at week 7 after starting cinnamaldehyde (8 weeks after surgery). The extent of cardiac hypertrophy was evaluated by pathological and molecular analyses of heart samples. Meanwhile, the effect of cinnamaldehyde on myocardial hypertrophy, fibrosis and dysfunction induced by AB was investigated, as was assessed by heart weigh/body weight, lung weight/body weight, heart weight/tibia length, echocardiographic and haemodynamic parameters, histological analysis, and gene expression of hypertrophic and fibrotic markers. Results: Our data demonstrated that echocardiography and catheter-based measurements of hemodynamic parameters at week 7 revealed the amelioration of systolic and diastolic abnormalities by cinnamaldehyde intervention. Cardiac fibrosis in AB mice was also decreased by cinnamaldehyde. Moreover, the beneficial effect of cinnamaldehyde was associated with the normalization in gene expression of hypertrophic and fibrotic markers. Further studies showed that pressure overload significantly induced the activation of extracellular signal-regulated kinase (ERK) signaling pathway, which was blocked by cinnamaldehyde. Conclusion: Cinnamaldehyde may be able to retard the progression of cardiac hypertrophy and fibrosis, probably via blocking ERK signaling pathway.     

Exercise-induced physiological hypertrophy initiates activation of cardiac progenitor cells

Objective: Physiological hypertrophy is featured by the hypertrophy of pre-existing cardiomyocytes and the formation of new cardiomyocytes. C-kit positive cardiac progenitor cells increased their numbers in exercise-induced physiological hypertrophy. However, the participation of Sca-1 positive cells in the physiological adaptation of the heart to exercise training is unclear. Methods: Physiological hypertrophy was induced by swimming and the mRNA levels of GATA binding protein 4 (GATA4), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), endogenous hepatocyte growth factor (HGF), and insulin like growth factor-1 (IGF-1) from the whole heart were determined by real-time polymerase chain reactions (RT-PCRs) analysis. Immunofluorescent staining was used to compare the number of C-kit and Sca-1 positive cardiac progenitor cells. In addition, mRNA levels of C-kit and Sca-1 in left ventricle (LV), right ventricle (RV), and outflow tract (OFT) were determined in mice swimming for 7, 14, and 21 days by RT-PCRs. Results: The ratio of heart weight (HW) to body weight and HW to tibia length and the mRNA level of GATA4 were increased while mRNA levels of ANP and BNP remained unchanged. C-kit and Sca-1 positive cardiac progenitor cells were activated by swimming training. An increased endogenous production of HGF and IGF was observed at least at the mRNA level. Swimming induced a significant up-regulation of C-kit in LV of mice swimming for 1, 2 and 3 weeks and in RV of mice swimming for 3 weeks. Sca-1 positive cardiac progenitor cells were increased in LV and OFT in mice swimming for 3 weeks. Conclusion: This study presents that swimming-induced physiological hypertrophy initiates activation of cardiac progenitor cells.     

Exercise preconditioning attenuates pressure overload-induced pathological cardiac hypertrophy

Pathological cardiac hypertrophy, a common response of the heart to a variety of cardiovascular diseases, is typically associated with myocytes remodeling and fibrotic replacement, cardiac dysfunction. Exercise preconditioning (EP) increases the myocardial mechanical load and enhances tolerance of cardiac ischemia-reperfusion injury (IRI), however, is less reported in pathological cardiac hypertrophy. To determine the effect of EP in pathological cardiac hypertrophy, Male 10-wk-old Sprague-Dawley rats (n=30) were subjected to 4 weeks of EP followed by 4-8 weeks of pressure overload (transverse aortic constriction, TAC) to induce pathological remodeling. TAC in untrained controls (n=30) led to pathological cardiac hypertrophy, depressed systolic function. We observed that left ventricular wall thickness in end diastole, heart size, heart weight-to-body weight ratio, heart weight-to-tibia length ratio, cross-sectional area of cardiomyocytes and the reactivation of fetal genes (atrial natriuretic peptide and brain natriuretic peptide) were markedly increased, meanwhile left ventricular internal dimension at end-diastole, systolic function were significantly decreased by TAC at 4 wks after operation (P < 0.01), all of which were effectively inhibited by EP treatment (P < 0.05), but the differences of these parameters were decreased at 8 wks after operation. Furthermore, EP treatment inhibited degradation of IκBα, and decreased NF-κB p65 subunit levels in the nuclear fraction, and then reduced IL2 levels in the myocardium of rats subject to TAC. EP can effectively attenuate pathological cardiac hypertrophic responses induced by TAC possibly through inhibition of degradation of IκB and blockade of the NF-κB signaling pathway in the early stage of pathological cardiac hypertrophy.     

血管紧张素-(1-7)对心肌肥厚的影响及其与细胞外信号调节激酶的关系

目的：探讨血管紧张素-(1-7)［Ang-(1-7)］对压力负荷性心肌肥厚的影响及其与细胞外信号调节激酶1/2(ERK1/2)的关系。 方法： 采用腹主动脉缩窄术复制心脏压力负荷增高大鼠模型。75只SD大鼠随机分为假手术组、模型对照组、Ang-(1-7)治疗组。在腹主动脉缩窄术后1 d开始，Ang-(1-7)治疗组大鼠，经置入式微量泵持续颈静脉给予Ang-(1-7) (25 μg·kg-1·h-1)；假手术组及模型对照组经微量泵只给予同量的生理盐水。各组分别于术后1周、术后4周处死部分大鼠，检测左心室重量/体重比、血浆及心肌血管紧张素Ⅱ浓度，并采用免疫印迹方法检测大鼠心肌中磷酸化ERK1/2(p-ERK1/2)表达水平。 结果： 术后1周和4周，腹主动脉缩窄均导致心肌血管紧张素Ⅱ浓度升高、左心室重量/体重比增加，也导致了心肌中p-ERK1/2表达增高；血管紧张素-(1-7)治疗未改变腹主动脉缩窄对心肌血管紧张素Ⅱ浓度的影响，但能明显减轻腹主动脉缩窄所诱导增高的左心室重量/体重比和心肌中p-ERK1/2表达水平。 结论： 外源性Ang-(1-7)可减轻压力负荷增高所致的心肌肥厚，这一作用可能与它抑制心肌p-ERK1/2表达有关。